Method for making a biodegradable stent

ABSTRACT

A method for making a biodegradable stent for insertion into a lumen, the method involves the casting of a film including a matrix of collagen IV and laminin, drying the film, casting a film containing polylactic acid onto the first dried film to form stent material, drying the material formed and forming the biodegradable material into a stent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Ser. No. 08/561,374,filed Nov. 21, 1995, now U.S. Pat. No. 5,769,883, which is a divisionalapplication of Ser. No. 08/372,822, filed Jan. 13, 1995, now U.S. Pat.No. 5,500,013, issued Mar. 19, 1996, which is a file wrappercontinuation application of Ser. No. 08/042,412, filed Apr. 2, 1993, nowabandoned, which is a continuation-in-part of Ser. No. 07/944,069, filedSep. 11, 1992, now abandoned, which is a continuation-in-part of Ser.No. 07/771,655, filed Oct. 4, 1991, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a device for providing mechanical support anda uniform release of drugs to a vessel lumen of a living being.

A variety of medical situations requires the use of a mechanism toexpand and support a constricted vessel and to maintain an openpassageway through the vessel. A few examples of such situationsfollowing angioplasty include holding a dissection in place, preventingclosure during spasm, and preventing acute closure due to thrombosis. Inthese situations, devices, commonly known as stents, are useful toprevent stenosis of a dilated vessel, or to eliminate the danger ofocclusion caused by "flaps" resulting from intimal tears that may beassociated with angioplasty, or to hold two ends of a vessel in place.

Stents have been made using materials of varied composition andconformation. McGreevy et al. U.S. Pat. Nos. 4,690,684 and 4,770,176,describe a meltable stent that is inserted into the interior of the endsof a blood vessel during anastomosis. Anastomosis refers to the surgicalor physical connection of two tubular structures, such as veins orarteries. The stent is made of blood plasma, which is biologicallycompatible with the living being and which melts rapidly in response toheat.

The Fischell et al. U.S. Pat. No. 4,768,507, describes an intravascularstent which is an unrestrained coil spring having an outside diameter of2 to 12 millimeters and a length of 5 to 25 millimeters. The materialsof construction are stainless steel, and a titanium alloy. Decreasedthrombogenicity is achievable by coating the outside of the coil with anon-thrombogenic material such as ULTI carbon.

The Leeven et al. U.S. Pat. No. 4,820,298, describes a stent having aflexible tubular body made from a thermal plastic to the form of ahelix. Polyester and polycarbonate copolymers are selected asparticularly desirable materials.

The Wolff et al. U.S. Pat. No. 4,830,003, describes a stent made fromwires formed into a cylinder. The wires are made of a biocompatiblemetal. Biocompatible metals include 300 series stainless steels such as316 LSS, as well as platinum and platinum-iridium alloys,cobalt-chromium alloys such as MP35N, and unalloyed titanium.

The Wiktor U.S. Pat. No. 4,886,062, describes a stent made from lowmemory metal such as a copper alloy, titanium, or gold. The stent ispreformed into a two-dimensional zig-zag form creating a flat expandableband.

The Gianturco U.S. Pat. No. 4,907,336, describes a wire stent having acylindrical shape that results from an expandable serpentineconfiguration. Malleable materials of construction are preferablyincluded from the group of annealed stainless steels, tungsten andplatinum.

Goldberg et al., Canadian Application 2,025,626, describe abio-degradable infusion stent used to treat ureteral obstructions. Theapplication describes an extruded material of construction made ofepsilon-caprolactone (15-25% w/w of terpolymer composition); glycoside(5-50% w/w) and L(-)lactide (45-85% w/w). This material was described ashaving a minimum tensile strength of at least 500 pounds per squareinch, preferably 650 psi; elongation of greater than 10%, preferablygreater than 100%; and Shore A hardness equal to 50-100%, preferably75-95%. The Goldberg et al. patent application describes a method forincorporating radiopaque materials such as barium sulfate into thepolymer in amounts ranging from 5-30%. The mechanism of biodegradationis described as hydrolysis resulting in degradable products excreted inurine or reabsorbed into tissues. The duration of functional life of thestent is estimated at about 3-7 weeks.

The Wilcoff U.S. Pat. No. 4,990,155, describes a plastic stent having aninherently expandable coil conformation. The "inherency" results from anelastic memory conferred by electron beam radiation impartingcross-linkages that provide an inherent tendency to return to a givendiameter after any distortion. Materials of construction include highdensity polyethylene. Optionally, this material is compounded with ananti-coagulant and/or an x-ray opaque material such asbismuth-sub-carbonate.

The Shockley et al. U.S. Pat. No. 4,994,033, describes a drug deliverydilatation catheter having three flexible, plastic tubes concentricallyarranged relative to each other. The outermost sleeve of this cathetercontains microholes for drug delivery. These microholes are made with alaser beam. Drugs that can be delivered by this system include aspirin,persantin, heparin, and prostaglandins. Drugs are delivered whenexternally applied pressure causes the innermost sleeve to balloon out.The drug is then forced through the microholes to spray and to treat alesion.

Sigwart, Canadian Patent Application 2,008,312, describes a stent madefrom a malleable flat sheet having a reticulated pattern. Thereticulated pattern includes non-deformable squares or diamonds. Thestent is made by rolling the sheet and locking the sheet into a spiralhaving a small diameter. The sheet is locked into a spiral by a tieinterwoven into the reticulated pattern. Once inserted into the lumen ofa vessel, the spiral is expanded and held in place by flaps integratedinto the outer body of the stent.

The Kawai et al. U.S. Pat. No. 4,950,258, describes a biodegradablemolded product having a first shape. The molded product is deformed atan elevated deforming temperature to form a second shape. The product isthen cooled. When the product is reheated to a prescribed temperature,the product recovers the first shape.

The Brandley et al. U.S. Pat. No. 5,032,679, describes aglycosaminoglycoside (GAG) composition made of tetrasaccharide unitsderived from heparin/heparin sulfate. The composition has use inpreventing proliferation of smooth muscle cells.

The Mares et al. U.S. Pat. No.5,061,281, describes a medical device madefrom a resorbable homopolymer derived from the polymerization of analphahydroxy carboxylic acid. The resorbable homopolymer has an averagemolecular weight of from 234,000 to 320,000 as measured by gelpermeation chromatography.

The Sinclair U.S. Pat. No. 4,057,537, describes a copolymer prepared bycopolymerizing an optically active lactide and epsilon caprolactone inthe presence of a tin ester of carboxylic acid. The copolymer isbiodegradable.

The Seilor, Jr. et al. U.S. Pat. No. 4,550,447, describes a porous tubefor use in a lumen of a vessel. The porous tube includes ribs foringrowth. Pores of the porous tube promote tissue ingrowth.

The Spears U.S. Pat. No. 4,799,479, describes the use of a heatedballoon to fuse tissue of a blood vessel. The balloon is heated by alaser.

The Spears U.S. Pat. No. 5,092,841, describes the use of a heatedballoon to bond a bioprotective material to an arterial wall. Thebioprotective material permeates into fissures and vessels of thearterial wall.

The Sawyer U.S. Pat. No. 5,108,417, describes a stent made from ahelically shaped titanium or aluminum strip having an airfoil on aninterior surface. The airfoil increases blood flow velocity through thestent.

The Hillstead U.S. Pat. No. 5,116,318, describes a dilation balloonassembly that includes an expandable sleeve. The expandable sleeve,positioned around a balloon of the assembly, eliminates a formation of"blade-like" edges on the balloon.

The Savin et al. U.S. Pat. No. 4,950,227, describes a stent deliverysystem that includes a pair of expandable cuffs that are positioned overopposing ends of a stent. The stent is positioned around a balloonattached to a catheter. The cuffs are positioned around the catheter sothat when the balloon expands, expanding the stent, the stent isreleased from the cuffs.

Cox et al. in Coron. Artery Dis. 3 at 3 (1992) describe a tantalum stentthat is balloon expandable and is coated with a cellulose ester. Thecellulose ester includes methotrexate, heparin or a combination of bothdrugs.

The stents mentioned do not remedy all problems relating to stents. Inparticular, some uses require stents to safely degrade within thebloodstream of an artery or vein over a period of weeks to months. Suchstents must meet particular criteria. For instance, such stents must becompatible with surrounding tissue in the vein or artery as well as withblood flowing through the vein or artery. Degradation products must beprevented from forming emboli.

Stents should also optimize flow through a vein or artery. Additionally,there is a need for stents which deliver agents or drugs to bloodpassing through the vein or artery that are generally beneficial to therecipient. Also desired are stents which can deliver drugs orbiologically active agents at a controlled rate to blood passing throughthe vessel lumen as well as to the vessel wall.

SUMMARY OF THE INVENTION

The present invention includes a biodegradable stent having a tubularmain body made of a matrix, essentially saturated with drugs, thatincludes collagen IV and laminin. The matrix is strengthened with astrengthening biodegradable material such as polylactic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an enlarged perspective view of one embodiment of the stent ofthe present invention.

FIG. 2 is a cross-sectional view of the stent.

FIG. 3 is an overview of one embodiment of opposing edges bounding aslot extending lengthwise along the main body of the stent of thepresent invention.

FIG. 4 is an enlarged perspective view of a coiled stent embodiment ofthe present invention.

FIG. 5 is a cross-sectional view of a main body of the coiled stentembodiment of the present invention.

FIG. 6 is a cross-sectional view of one embodiment of a main body of thebiodegradable coiled stent of the present invention.

FIG. 7 is a schematic view of a collagen IV tetramer.

FIG. 8 is an enlarged cross-sectional view of an outer surface of oneembodiment of the biodegradable coiled stent of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention includes a biodegradable stent generallyillustrated at 10 in FIG. 1. The stent 10 releases drugs into a tubularvessel 12 having a lumen 13 in a living being. The rate of drug releaseis controlled by the rate of degradation of the biodegradable materials.The stent 10 also provides mechanical support to a tubular vessel 12 ina living being. The stent strengthens an area of the vessel that is incontact with the stent 10.

The stent 10 includes a generally tubular main body 11 and a pluralityof fibers 18 disposed around the main body 11. A plurality of apertures14 extend through the stent 10. The stent 10 also includes a slot 26extending the length of the stent.

The tubular main body 11 includes an outer surface 16 and inner surface22. The outer surface 16 of the main body 11 faces an inner surface wall24 of the vessel 12. The inner surface 22 of the stent 10 faces a streamflowing through the lumen 13 as shown in cross section in FIG. 2. Thestent of the present invention may range from 1 millimeter in diameterto 50 millimeters in diameter and from 1 millimeter in length to 50millimeters in length. The size of the stent is dictated by the lumen ofthe vessel to which the stent is placed. The tubular main body suitablyhas a length of up to approximately 5 centimeters.

The plurality of fibers 18 disposed around the main body 11 contacts theouter surface 16 of the main body. In one preferred embodiment, thefibers are arranged concentrically around the main body, encircling theouter surface 16 in an annular alignment. The annular alignment isordered so that individual fibers are separated by approximately thesame distance. Alternatively, the fibers are arranged in annular pairsor triplets. In another embodiment, the plurality of fibers abut eachother in annular alignment.

In another embodiment, the plurality of fibers 18 of the outer surfaceare braided. Braided fibers are also arranged in annular alignmentaround the main body of the stent 10. In one other embodiment, thefibers are woven. Woven fibers increase the stretch and flexibility ofthe stent compared to fibers which are not woven. Solid fibers, hollowfibers, or a combination thereof can be used for any of the embodimentsdescribed above.

The plurality of fibers 18 of the main body 11 can be formed bytechniques well known in the art. These techniques include melt, wet anddry spinning. High molecular weight polymers having a range of 200,000to 3,000,000 daltons are preferred for successful fiber production. Oneexample of a biodegradable material meeting this criterion for fibermanufacture is poly-L-lactide.

The fibers generally undergo further orientation in the extrudeddirection. One technique for orienting the fibers is to stretch thefibers at a temperature range of 50° to 150° C.

Desirably, the plurality of fibers 18 disposed around the main body 11of the stent 10 have an outer diameter not exceeding approximately 0.2millimeters. In the case of hollow fibers, the wall thicknesses shouldbe within the approximate range of 25 to 100 microns. Preferably, thefibers should have a tensile strength in a range of 4,000 to 500,000pounds per square inch and have a modulus of 200,000 to 2,000,000 poundsper square inch.

In one embodiment, the main body includes a film that is preferablycombined with the plurality of fibers disposed around the main body 11.The film combined with the plurality of fibers defines the outer surface16 of the main body. The plurality of fibers can be combined with thefilm using any number of conventional methods. In one conventionalmethod, solvation sealing, the steps of heat pressing and extrusionmolding combine the film and fiber production into one step for theorientation of the polymer materials. Additional methods include solventsealing of the fibers to the film or heat melting processes for theannealing of the multiple layers. By the solvation sealing method,fibers and film are combined to form the outer surface into a singlebiodegradable material matrix.

Preferably, the main body 11 of the stent 10 includes a film 32,covering the inner surface 22. The film 32 of the inner surface 22 isformed by conventional methods such as heat or pressure extrusion orsolution casting.

Additionally, the present invention includes an embodiment where theinner surface 22 and the outer surface 16 of the main body 11 areseparated by at least one interior film layer. The interior film layeris integrated into the main body by multiple casting with the inner andouter surfaces. The present invention further includes a main bodyhaving more than one biodegradable interior film layer. Desirably, thethickness of the main body does not exceed approximately 0.25millimeters.

The plurality of apertures of the present invention is preferablyordered around the main body to form rows of apertures. FIG. 1illustrates two rows of apertures, the length of each row extending thelength of the tubular main body. In an alternative embodiment, theplurality of apertures are ordered to form one row having a lengthextending the length of the tubular main body. The apertures within theone row are bounded by edges 28 and 30 bordering the slot 26. In oneother embodiment, the plurality of apertures are ordered to form a rowextending less than the length of the main body of the stent. In anotherembodiment, the plurality of apertures are not ordered but are locatedrandomly over the main body of the stent.

Suitable shapes for the individual apertures include both asymmetricaland symmetrical shapes such as ovals, circles, or rectangles. Also,apertures may be made in a variety of sizes. The apertures can be formedby any conventional means such as stamping.

The slot 26 extends the length of the stent and is defined by opposingedges 28 and 30 of the main body as illustrated in FIG. 3. In apreferred embodiment, the fibers 18 are oriented fibers and are fixed tothe outer surface 16 of the main body 11. When the slot 26 is formed,the oriented fibers 18 provide a spring force in an outwardsubstantially radial direction. The outward spring force increases theeffective diameter of the main body while the slot permits compressionor reduction of the effective diameter. Once formed, the stent isnormally at its effective maximum diameter and the slot is at itswidest.

In use, the stent is positioned at the inner surface wall 24 of thevessel 12 by radially compressing the stent to a tubular diameter lessthan the diameter of the vessel 12 and moving the stent to a desiredsite within the vessel. The stent is secured by releasing the stent fromcompression so that the stent can radially spring out to abut againstthe inner surface wall 22 of the vessel 12.

In the most preferred embodiment, the biodegradable stent of the presentinvention is made of biodegradable materials that are alsobiocompatible. By biodegradable is meant that a material will undergobreakdown or decomposition into harmless compounds as part of a normalbiological process. It is important to the present invention that theplurality of apertures 14 in the main body 11 of the stent promote thesuccessful biodegradation of the stent 10. Optimally, the plurality ofapertures 14 permits epithelial cells to grow on the stent 10. It isbelieved that the epithelial cell growth will encapsulate particles ofthe stent during biodegradation that would otherwise come loose and formemboli in the bloodstream.

Suitable biodegradable materials for the main body 11 of the stent 10 ofthe present invention include polylactic acid, polyglycolic acid (PGA),collagen or other connective proteins or natural materials,polycaprolactone, hylauric acid, adhesive proteins, co-polymers of thesematerials as well as composites and combinations thereof andcombinations of other biodegradable polymers. Biodegradable glass orbioactive glass is also a suitable biodegradable material for use in thepresent invention. Preferably the materials have been approved by theU.S. Food and Drug Administration.

The present invention includes a biodegradable stent incorporating avariety of biodegradable materials within it. For instance, in oneembodiment, the film and fibers covering the inner surface 22 of themain body 11 of the biodegradable stent is made of either polylacticacid, polyglycolic acid (PGA), collagen or other connective proteins ornatural materials, polycaprolactone, copolymers of these materials aswell as composites thereof and combinations of other biodegradablepolymers. The film covering the outer surface 16 along with theplurality of fibers 18 are made of either collagen, hylauric acid,adhesive proteins, copolymers of these materials as well as compositesand combinations thereof. The present invention includes an embodimentwhere fibers are made from more than one biodegradable material. Also,the present invention includes an embodiment where the film is made froma biodegradable material different from the fibers.

One other embodiment of the biodegradable stent of the present inventionincludes a biodegradable coiled stent, illustrated at 50 in FIG. 4. Thecoiled stent 50 includes a main body strip 58 made of a biodegradablematerial, having an exterior surface 56, a cambered interior surface 54,a leading end 66 and a trailing end 68 opposing the leading end. Thebiodegradable coiled stent 50 is most preferably helically coiled.

The biodegradable coiled stent 50 most preferably has alength-to-diameter ratio of at least about 1-to-2. Thelength-to-diameter ratio of at least about 1-to-2 prevents the coiledstent from flipping out of position and tumbling through the lumen. Inone embodiment, the coiled stent 50 has a length of at least about 3 mm.The main body strip 58 of the coiled stent 50 is preferably made from astrip of biodegradable material having a width of about 2 millimeters.

The main body strip 58 is most preferably formed into a plurality ofindividual, integral coils as shown at 62 and 64 to make the coiledstent 50. The individual, integral coils 62 and 64 are spaced to permitepithelial cells to grow on the coiled stent 50.

The exterior surface 56 of the main body strip 58 faces the lumen of thevessel. The exterior surface 56 is preferably textured by a plurality ofpores (not shown). The plurality of pores are sized and positioned inorder to promote adhesion of the coiled stent 50 to the vessel wall.Specifically, the pores are sized to promote ingrowth of cells of thevessel wall onto the exterior surface 56. In one embodiment, the poreshave a diameter within a range of about 0.1 to 30.0 microns and anapparent density of about 10 to 70% of a nonporous material density.

The cambered interior surface 54 of the main body strip 58 contacts thefluid stream passing through the lumen of the vessel once the strip 58has been coiled and inserted into the lumen. The cambered interiorsurface 54 is preferably symmetrical and smooth. The cambered interiorsurface 54 of the main body strip 58 includes a camber 60, mostpreferably having a maximum angle of curvature within a range of about10 to 20 degrees. The camber 60 extends outwardly, into the fluidstream, in a convex fashion as shown in cross-section in FIG. 5.

The leading end 66 of the main body strip 58 faces a direction of flowof fluid passing through the vessel lumen. The trailing end 68 opposesthe leading end 66. Most preferably, the main body strip 58 has athickness that is substantially the same at the leading end 66 as at thetrailing end 68. In one preferred thickness profile embodiment for themain body strip 58 illustrated in FIG. 5, the main body 58 has a minimumthickness at the leading end 66 and trailing end 68. Preferably, thethickness is symmetrically tapered to approach zero microns at each ofthe leading end 66 and trailing end 68.

The cambered interior surface 54, the leading end 66 and the trailingend 68 together prevent the formation of eddys, formed in a wake that ismade when a fluid such as blood passes through each coil 62 and 64 ofthe coiled stent 50. The cambered interior surface 54, leading end 66and trailing end 68 are also believed to reduce the wake size for eachcoil 62 and 64 and are believed to reduce pressure drag on each coil 62and 64.

To install in a lumen of a vessel, the coiled stent 50 is positioned ata wall (not shown) of the lumen by radially compressing the stent to atubular diameter less than the diameter of the vessel and moving thestent 50 to a desired site within the vessel. The stent 50 is secured byreleasing the stent 50 from compression so that the stent 50 canradially spring out to abut against the wall of the vessel.

In one installation embodiment, the biodegradable coiled stent 50includes a plurality of microcapsules that are dispersed in thebiodegradable material. The microcapsules contain a material thatinduces crosslinking of the biodegradable material. The biodegradablestent including the plurality of microcapsules is further expanded whilein the lumen and is heated with a heated balloon and is cooled while thestent is in an expanded position.

The balloon contacts the cambered interior surface 54 of the coiledstent 50 and heats the stent with a magnitude of thermal energy thatwill cause the microcapsules to burst and release the material thatinduces crosslinking. Crosslinking the biodegradable material imparts astrength to the stent sufficient to hold open the lumen.

The thermal energy will not be of a magnitude great enough to changesurrounding lumen tissue. In particular, the thermal energy will noteither fuse lumen tissue or cause a bonding of tissue with the stent. Tothe contrary, it is important to the coiled stent embodiment 50 of thepresent invention that thermal energy from the balloon not change livinglumen tissue.

The thermal energy includes energy derived from heated fluids,electromagnetic energy and ultrasonic energy. In one embodiment, thethermal energy heats the biodegradable material of the stent to atemperature above a glass transition temperature of the biodegradablematerial but below a melting point of the material.

In one other embodiment, the thermal energy heats the biodegradablematerial of the stent to a first temperature that is lower than theglass transition temperature of the biodegradable material. Then, thestent is heated to a second temperature above the glass transitiontemperature of the biodegradable material.

Once the biodegradable material of the stent is heated above its glasstransition temperature, the material softens. The balloon is thenexpanded. The expanded balloon radially enlarges the diameter of thestent. The stent, having an enlarged diameter, is then allowed to coolin an expanded position and the balloon is removed. In one otherembodiment, the stent is expanded by the balloon before being heated toa temperature above the glass transition temperature of itsbiodegradable material.

The present invention includes one other installation embodiment for abiodegradable stent having a biodegradable tubular main body. Thebiodegradable tubular main body is made of a deformable, biodegradablematerial that overlays a balloon of a catheter. When the deformable,biodegradable material overlays the balloon, the material assumes ashape of the tubular main body. Acceptable tubular shapes include aslotted tubular shape as shown in FIG. 1 and a helically coiled shape asshown in FIG. 4. The deformable, biodegradable material is preferablycoated with a biodegradable, biocompatable film that adheres thebiodegradable material to the balloon.

In one embodiment, the biodegradable film forms a water soluble, viscousinterface between the tubular main body and the balloon when wetted. Thefilm gradually dissolves in a water component of blood while passingthrough the lumen. The biodegradable film dissolves at a rate thatpermits adherence of the tubular main body to the balloon by the filmduring passage of the stent and balloon through the lumen and during anexpansion of the balloon and the tubular main body. However, the film isdissolved once the stent is expanded to a degree that permits the stentto be separated from the balloon. The water soluble film is acceptablymade from materials that include high molecular weight polyethyleneglycol, high molecular weight carbohydrates and high molecular weightpolyvinylpyrrolidone. The water soluble film also acceptably includes anantithrombic drug to aid in the reduction of thrombosis.

In another embodiment, the biodegradable, biocompatable film is meltableupon application of thermal energy. The meltable film is acceptably madefrom ionic, crosslinked polymers that include combinations of anioniccarbohydrates with polycations.

The balloon of the catheter, having the biodegradable tubular main bodyadhered, is positioned within the lumen at a site where the tubular mainbody of the stent is to be installed. Once positioned, the balloon isexpanded, radially expanding the diameter of the tubular main body. Thebiodegradable tubular main body is then heated to a temperature abovethe glass transition temperature and below a melting temperature of thebiodegradable material, softening the biodegradable material of thetubular main body. Heating the tubular main body also melts the meltablefilm coating of the tubular main body, permitting release of the tubularmain body from the balloon.

The source of energy for heating the tubular main body is suitablyderived from heated fluids, electromagnetic energy and ultrasonicenergy. In one embodiment, a fluid contained in the balloon is heated bya heating element also contained in the balloon.

The tubular main body is subsequently allowed to cool. Once the mainbody is cooled, the balloon is deflated and removed from the lumen. Thecooled and strengthened biodegradable stent remains in the lumen.

The present invention also includes embodiments where the deformable,biodegradable material of the tubular main body is strengthened by anapplication of mechanical energy. In one embodiment, the mechanicalenergy is applied to the tubular main body to reorient molecules of thebiodegradable material of the stent. The mechanical energy is applied ata temperature below a glass transition temperature of the material. Themechanical energy is of a magnitude below an elastic limit of thebiodegradable material.

In another embodiment using mechanical energy, the biodegradablematerial of the tubular main body includes the plurality ofmicrocapsules. The microcapsules include materials that inducecrosslinking in the biodegradable material. The mechanical energy isapplied to the tubular main body in order to burst the microcapsules.Once burst, the microcapsules release the materials that inducecrosslinking of the biodegradable material. The biodegradable materialis then crosslinked and is strengthened.

The mechanical energy is applied by inflating the balloon to which thetubular main body is adhered. Inflating the balloon radially expands andstretches the deformable, biodegradable material of the tubular mainbody. The stretching is of a magnitude to reorient molecules of onestent embodiment. The stretching is also of a magnitude to burstmicrocapsules contained in the biodegradable material of the secondembodiment.

In one embodiment of the biodegradable coiled stent 50, the main body 58is made from a single individual biodegradable material such aspolylactic acid (pla). Preferably, the pla has a low degree ofpolymerization (dp).

In one other embodiment, the main body 58 is made from a plurality ofindividual, biodegradable materials arranged in layers. Each of theindividual, biodegradable layers has distinct physical and chemicalproperties.

In one layered embodiment of the coiled stent 50, an inner layercontacting the fluid passing through the vessel lumen, is made of eitherpolylactic acid, polyglycolic acid (PGA), collagen or other connectiveproteins or natural materials, polycaprolactone, copolymers of thesematerials as well as composites thereof and combinations of otherbiodegradable polymers. An outer layer, contacting a wall of the vessellumen, is made of either collagen, hylauric acid, adhesive proteins,copolymers of these materials as well as composites and combinationsthereof.

One particular embodiment of the coiled stent, illustrated at 100 inFIG. 6, is made of a matrix 101 that includes. collagen IV and laminin.In one embodiment, the matrix 101 also includes heparin.

The matrix 101 includes essentially quasi-crystalline regions 102 havinginterfaces 103 with collagen IV concentrated at the interfaces 103. Theinterfaces 103 of collagen IV enclose voids 105 within the matrix 101.

The type IV collagen component of the matrix 101 is a highly specializedform of collagen protein found primarily in basement membranes. The typeIV collagen protein molecule has a tertiary structure unlike any othercollagen type. It is believed that the tertiary structure of type IVcollagen is a tetramer formed by four triple-helical collagen molecules,such as is illustrated at 120 in FIG. 7. The triple-helical collagenmolecules form arms 122 of the tetramer 120. The arms 122 function asflexible spacers. Each triple-helical collagen molecule overlaps at anamino terminii to form a 7 S collagen fragment at a center 124 of thetetramer 120. The 7 S collagen fragment is a disulfide fragment that isresistant to collagenase enzyme. Also, a C-terminal globular domain (notshown) of the type IV collagen molecule is included as an integral partof the final collagen IV matrix 101.

The type IV collagen tetramers form the quasi-crystalline regions 102within the matrix 101. The quasi-crystalline regions 102 have anirregular polygonal structure formed from the tetragonal tertiarystructure of the collagen IV molecules.

Within the matrix 101, the collagen IV tetramers are connected to oneanother via their amino-termini 125. Flexibility of thequasi-crystalline regions of the matrix 101 is introduced by a frequentinterruption of a particular amino acid sequence, (Gly-X-Y)n, within thetriple helical arms 122 of the collagen IV tetramers 120. The amino acidsequence interruption disrupts the triple helical configuration of thearms 122.

The role of laminin as a component of the matrix 101 is believed to beone of aiding in the organizing of the collagen IV and heparin to formthe matrix 101. Laminin is a glycoprotein having two or three shortchains, each having a molecular weight of about 200,000 daltons and onelong chain having a molecular weight of about 400,000 daltons. Thechains are held together by disulfide bonds. Electron microscopy ofrotary shadowed laminin has revealed that laminin has a cross-shapedstructure with rodlike segments and globular domains.

Laminin binds the components of collagen IV and heparin to make thematrix 101. Specifically, laminin includes collagen IV binding sites onthe short chains and a heparin binding site at a globular end of thelong chain. In addition to binding collagen IV and heparin, laminin aidsin organizing the matrix 101. Laminin also promotes an attachment ofepithelial cells to type IV collagen-coated substrates.

The heparin component of the matrix 101 is a glycosaminoglucuronan (gag)having a molecular weight within a range of about 6000 to 25,000molecular weight units. The heparin component binds with laminin to makethe matrix 101 of the stent 100 of the present invention. The presentinvention acceptably includes moieties of the glycosaminoglycoside groupin addition to heparin. The moieties include residues of D-glucuronicacid.

In one other embodiment, the stent 100 includes polylactic acid havingcrystalline regions. The matrix 101 made of collagen IV and laminin,when wet, has a strength that is not sufficient to hold open the lumenof the vessel of the living being. The polylactic acid impartsstructural integrity to the stent 100.

In one embodiment, the polylactic acid is interspersed as particleswithin the matrix 101 (not shown) to strengthen the matrix 101. In oneother embodiment, the polylactic acid is positioned on the outer surface114 of the stent 100 as a layer 107.

In one preferred embodiment, the matrix 101 is essentially saturatedwith drugs. The drugs are included within the voids 105 within thequasi-crystalline membrane matrix 101, particularly if the drugs arehydrophilic. In one embodiment, the drugs are included within thepolylactic acid polymer, particularly if the drugs are hydrophobic.

In one embodiment, the drugs are in a liquid phase and are mixed to forma liquid drug mixture. The drug mixture is used to substantially fillthe voids 105 within the matrix 101.

In one other embodiment, the drugs are included within microcapsules.The microcapsules may be added to any of the voids 105, the polylacticacid 107 and the collagen/laminin/heparin matrix 101.

In one further embodiment, the drugs include both a liquid phase and amicrocapsule phase. Both the liquid and the microcapsules are added tothe voids 105.

Preferably, the matrix 101 includes drugs performing particularfunctions within particular portions of the coiled stent 100. Forinstance, the stent 100 includes an inner portion 104 having a surface106 that interfaces with a vascular wall 108 of the lumen. This innerportion 104 and surface 106 are essentially saturated with drugs thatare released as the matrix 101 degrades. The drugs that are releasedpreferably include those promoting epithelial cell growth.

As the matrix 101 degrades, the inner portion 104 recedes. The innersurface 106 also recedes and releases drugs that promote epithelial cellgrowth until the inner portion 104 is biodegraded.

In one embodiment, the stent 100 includes a middle portion 110 thatincludes drugs that prevent an infiltration of cells. The middle portion110 includes drugs enclosed within voids 105 that inhibit the growth ofundesirable infiltrating cells. The drugs may also be included withinthe collagen/laminin matrix 101 or the polylactic acid.

The stent 100 also includes an outer portion 112 that includesantithrombogenic drugs. The antithrombogenic drugs are also includedwithin voids 105 of the matrix 101. The antithrombic drugs may also beincluded within the collagen/laminin matrix 101 or the polylactic acid.The outer portion 112 includes an outer surface 114 that faces a fluidflow passing through the lumen of the vessel.

In one embodiment, the outer surface 114 is irregular and delineatespores 118, such as are illustrated in FIG. 8. The irregular outersurface 114 is a consequence of the conformation of thequasi-crystalline structure of the matrix 101 used to make the outerportion 112. In one embodiment, the pores 118 are filled with a gel 119,made of collagen, such as is illustrated in FIG. 8.

The outer portion 112 most preferably includes an anti-coagulant,included within voids 105. In one embodiment, the gel 119 is impregnatedwith the anti-coagulant. The formulation of the gel 119 andanti-coagulant is preferably very slowly dissolving. The rate ofdissolution may be further slowed by a hydrolysis reaction that occursbetween the gel 119 and blood. The hydrolyzed gel provides a dissolutionbarrier 121 that dampens the rate of dissolution of the underlying gel119.

Two components of the matrix 101, the collagen IV and the polylacticacid, are hydrophobic and hydrophilic, respectively. Consequently, inone embodiment the collagen IV matrix is cast separately from thepolylactic acid. In one preferred manufacturing embodiment, a matrix ofcollagen IV/laminin/gag is cast and is permitted to thoroughly dry. Thematrix may then be plasma treated to improve the matrix receptivity tothe polylactic acid polymer. Once the matrix has dried, a solution ofpolylactic acid is cast onto the matrix. Once dried, the stent 100 iscut from the matrix and is coiled.

To make a tube embodiment, the collagen may be coated on a mandrel,dried, and dipped into a polymer solution. In one other embodiment, thepolylactic acid is particulated and is dispersed within the matrix ofcollagen IV/laminin and gag.

The stent 100 is installed in the lumen of a vessel by methodspreviously described for the coiled stent 50. In one embodiment, thepolylactic acid includes microcapsules containing a crosslinking agentthat is released when the microcapsules are ruptured. The microcapsulesare ruptured in situ, once the stent 100 is positioned at a desired sitein a lumen.

One advantage of using the variety of biodegradable materials within thetubular main body embodiment of FIG. 1, the coiled stent embodiment 50of FIG. 4, and the matrix stent 100 is control of degradation.Biodegradable materials degrade at different rates, ranging from weeksto several years. Consequently, the presence of different biodegradablematerials in the stent permits the stent to degrade in a predictable,orchestrated fashion.

The stent embodiments of the present invention further includeincorporation of a drug or drugs or other biologically active materials.The drugs are contained within the biodegradable materials of which thestent is composed. As the stent biodegrades, drugs are administered tothe surrounding tissue or to the blood stream. Thus, the rate of drugrelease is controlled by the rate of degradation of the biodegradablematerials. A material that degrades rapidly will release the drug fasterthan a material that degrades slowly.

Additionally, the rate of drug release can either accelerate or slowdown the rate of degradation of the biodegradable material. Thus, therate of release of a drug acts as a control quantity for the rate ofdegradation. For instance, one coiled stent embodiment could include acoiled main body made from a strip having four layers. A first layer,contacting the vessel wall, could incorporate the drug, fibronectin. Asecond layer contacting the first layer, could incorporate the drugfibronectin at a lower concentration than the first layer. A third layercontacting the second layer could incorporate fibronectin at a lowerconcentration than either the first or the second layer. A fourth layercould contact the fluid passing through the lumen and could incorporatethe drug, heparin.

The drug fibronectin accelerates growth of cells surrounding the stent.The accelerated growth of cells accelerates resorption reactions of thefirst layer of the stent. A reduced fibronectin concentration in thesecond and third layers slows down the resorption reactions so that thedegradation of the first three layers will proceed at a cumulative ratethat is compatible with the degradation of the fourth layer.

Drugs are incorporated into the biodegradable stent using techniquesknown in the art. The techniques include simple mixing or solubilizingwith polymer solutions, dispersing into the biodegradable polymer duringthe extrusion of melt spinning process, or coating onto an alreadyformed film or fiber. In one embodiment, hollow fibers, which containanti-thrombogenic drugs, are arranged in a parallel concentricconfiguration with solid fibers for added support for use on the outersurface 16 of the main body 11 of the stent 10.

Further, drugs can be incorporated into the film of both the inner andouter surfaces by using methods such as melting or solvation. If aninterior film layer is present within the main body as well, theinterior layer and inner and outer surfaces are then combined with eachother such as by mechanically pressing one layer to the other layer in aprocess augmented by heat or solvation adhesives. In another embodiment,drugs or biologically active agents are incorporated into the film layerand surfaces by entrapment between the layers and surfaces ofbiodegradable material sandwiched together, thereby further promotingrelease of the drugs or agents at different rates.

The drugs or other biologically active materials incorporated into thestent of the present invention perform a variety of functions. Thefunctions include but are not limited to an anti-clotting oranti-platelet function; and preventing smooth muscle cell growth on theinner surface wall of the vessel. The drugs include but are not limitedto drugs that inhibit or control the formation of thrombus orthrombolytics such as heparin or heparin fragments, aspirin, coumadin,tissue plasminogen activator (TPA), urokinase, hirudin, andstreptokinase, antiproliferatives (methotrexate, cisplatin,fluorouracil, Adriamycin, and the like) antioxidants (ascorbic acid,carotene, B, vitamin E, and the like), antimetabolites, thromboxaneinhibitors, non-steroidal and steroidal anti-inflammatory drugs, Betaand Calcium channel blockers, genetic materials including DNA and RNAfragments, and complete expression genes, carbohydrates, and proteinsincluding but not limited to antibodies (monoclonal and polyclonal)lymphokines and growth factors, prostaglandins, and leukotrienes. Thestent also incorporates bioactive materials such as fibronectin,laminin, elastin, collagen, and intergrins. Fibronectin promotesadherence of the stent to the tissue of the vessel 12.

In one specific example of a biodegradable material incorporating drugs,a poly-L-lactide having an intrinsic viscosity of 2.3 dl/g is used toform monofilament fibers using a spin or melt spinning process. Fivepercent aspirin or 5% heparin was incorporated into the melt of thepoly-L-lactide prior to fiber formation. The fibers formed had adiameter of approximately 0.5 millimeters. The monofilaments were thenstretched under temperatures ranging from 50° C. to 200° C. to orientthe fiber. The temperature employed depends upon the kind of materialused to make the fiber. The final diameter of the oriented fiber fallswithin a range of 0.1 to 0.3 millimeters. Similar processing was used toincorporate 5% aspirin or 5% heparin into poly-L-lactide andpolyglycolide.

Just as the use of a variety of biodegradable materials facilitates acontrolled degradation of the biodegradable stent, so similarly does theincorporation of a variety of drugs into the biodegradable materialsfacilitate control of drug release to perform a variety of functions.For instance, drugs released from the outer surface as the outer surfacedegrades facilitate adherence of the stent to the inner surface wall 24of the vessel 12. Drugs released from fibers perform a variety offunctions, ranging from promoting cell growth to altering the bloodclotting mechanisms, depending upon from what fiber the drug isreleased. In one embodiment, drugs released from the inner surface 22 ofthe stent as the inner surface degrades temper platelet function inblood flowing through the lumen 13.

The rate of release of drugs promoting cell growth has the capability ofincreasing the rate of degradation of the biodegradable stent byincreasing a rate of resorption. Similarly, the rate of release of drugspromoting cell growth has the capability of decreasing the rate ofdegradation by decreasing the rate of resorption. The stent of thepresent invention includes embodiments where drugs are incorporated in amanner that both increases and decreases the rate of degradation of thebiodegradable stent over the life of the stent.

Although the present invention has been described with reference topreferred embodiments, workers skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

What is claimed is:
 1. A method for making a biodegradable stent forinsertion into a lumen of a vessel of a living being, comprising:castinga film that includes a matrix of collagen IV and laminin; drying thefilm; casting a film that includes polylactic acid onto the dried filmthat includes the matrix of collagen IV and laminin to form a stentmaterial; drying the stent material; and forming the stent material intothe biodegradable stent.
 2. The method of claim 1 and further includingplasma treating the film including the matrix of collagen IV and lamininafter drying the film and before casting the film that includespolylactic acid onto the dried film.